Evolutionary characterisation of lung adenocarcinoma morphology in TRACERx

Lung adenocarcinomas (LUADs) display a broad histological spectrum from low-grade lepidic tumours through to mid-grade acinar and papillary and high-grade solid, cribriform and micropapillary tumours. Little is known as to how morphology reflects tumour evolutionary history and disease progression. Whole exome sequencing data generated from 805 primary tumour regions and 121 paired metastatic tumours across 248 LUADs from the TRACERx 421 cohort, as well as RNA-Seq data from 463 primary tumour regions, were integrated with detailed histopathological analysis of tumour morphology at the whole and regional tumour level. Tumours with predominantly high-grade architectural patterns showed increased chromosomal complexity, with higher levels of loss of heterozygosity (LOH) and subclonal somatic copy number alterations (SCNAs). Individual regions in predominantly high-grade pattern tumours tended to be highly proliferative and less clonally diverse, potentially reflective of large recent subclonal expansions. Co-occurence of truncal loss/LOH of chromosome 3p and 3q was enriched in predominantly low/mid-grade tumours, whilst purely undifferentiated solid pattern tumours had a higher frequency of truncal 3q gains and SMARCA4 gene alterations compared with other subtypes, including mixed solid pattern tumours, suggesting distinct evolutionary trajectories. Clonal evolution analysis revealed that tumours tend to evolve towards higher grade patterns. The presence of micropapillary pattern and ‘spread through air spaces’ (STAS) were associated with an increased risk of intra-thoracic-only recurrence, in contrast to the presence of solid/cribriform patterns, necrosis, and pre-operative circulating tumour DNA (ctDNA) detection, which were associated with increased risk of extra-thoracic recurrence. Overall, these data provide insights into the relationship between LUAD histological subtypes and their underlying evolutionary genomic landscape, as well as clinical risk and clonal nature of metastatic dissemination.